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Contents 1 Glutathione Peroxidase 1 2 Overview 3 Secondary Structure and the Thioredoxin Like Fold of GPx-1 4 GPx-1 and Disease 5 Other Proteins with a thioredoxin like fold 6 References

Glutathione Peroxidase 1

Overview

Glutathione peroxidase 1 (GPx-1) is a tetramer (23 kDa per monomer) with two units composed of dimers. GPx-1 is the most abundant member of the Glutathione peroxidase family. It is found in all cells and is located in the cytosolic and mitochondrial compartments (1). GPx-1 is a crucial anti-oxidant enzyme that catalyzes the conversion of hydrogen peroxide into water (2). Interestingly GPx-1 contains the rare amino acid selenocysteine which acts as the peroxidatic residue (2). The overall reaction that GPx-1 catalyzes is H2O2 + 2Glutathione (GSH) -> 2H2O + GS-SG (Figure 1) . In addition to hydrogen peroxide GPx-1 can reduce other soluble hydroperoxides including lipid hydroperoxides (3). Because of its role in regulating the intracellular concentration of reactive oxygen species, GPx-1 has been found to play a role in numerous processes including cell proliferation, apoptosis, and inflammation (1). Furthermore deficiencies in GPx-1 has been linked to the development of cancers, neurodegenerative diseases, and heart disease (4).

Secondary Structure and the Thioredoxin Like Fold of GPx-1

The secondary structure of GPx-1 consists of nine β-strands and nine α-helices with five of the helices being of the 310 form (Figure 2). Interestingly two of the β-strands form a parallel β-sheet (Figure 3). The overall fold of GPx-1 is similar to that of thioredoxin. The classic thioredoxin fold consists of a four stranded β-sheet that is surrounded by three α-helices (Figure 4) (5). However the thioredoxin fold is commonly subject to the insertion of additional secondary structural elements between the second β-strand and the second α-helices (6). This is seen in GPx-1 as there is an addition of an α-helix and a β-strand between the second β-strand and the second α-helices (Figure 5) (6). A similar insertion is found in peroxiredoxins, a different family of proteins which also catalyze the reduction of hydroperoxides (6).

GPx-1 and Disease

Because of its role as an anti-oxidant, deficiencies in GPx-1 have been linked to the pathogenesis of multiple diseases. These diseases include cancers, neurodegenerative diseases, heart disease, and diabetes (4). The Pathogenisis of these diseases have been linked to the presences of excessive reactive oxygen species (ROS) (7,8). One major oxidant is hydrogen peroxide which has been shown to oxidatively modify proteins and DNA bases as well as induce single and double stranded DNA breaks (9,10). Deficiencies in GPx-1 could result in excessive hydrogen peroxide and thus cellular damage giving rise to these disorders.

Other Proteins with a thioredoxin like fold

Proteins that have a thioredoxin like fold are involved in catalyzing reduction, oxidation, or disulfide bond exchanges (11). Thioredoxin is the protein after which the fold is named and is an important redox protein. Glutaredoxins are another class of proteins that have a thioredoxin like fold and are distantly related to thioredoxin. This family of proteins are also involved in maintaining the redox state of the cytosol (11). A third class of proteins with this fold are the disulfide oxidoreductases which are involved in catalyzing the formation of disulfide bonds and play an important role in protein folding (11). Glutathione peroxidases also have a thioredoxin like fold and are involved in the reduction of various oxidants which helps to modulate the intracellular redox state. Peroxyredoxins are also involved in the regulation of the intracellular redox state as they reduce various peroxides. A final class of proteins that contain a thioredoxin like fold are the glutathione-s-transferases which catalyze the transfer of glutathione to various substrates and which is an important step in the metabolism of various molecules (11).

References

1.Lubos E, Loscalzo J, Handy DE (2011). Glutathione Peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxidants & Redox Signaling 15 (7), 1958-1982.

2.Prabhakar R, Vreven T, Morokuma K, Musaev DG (2005). Elucidation of the mechanism of selenoprotein glutathione peroxidase (Gpx)-catalyzed hydrogen peroxide reduction by two glutathione molecules: a density functional study. Biochemistry 44, 11864-11871.

3.Marinho HS, Antunes F, Pinto RE (1997). Role of glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase in the reduction of lysophospholipid hydroperoxides. Free Radic Biol Med 22, 871-883.

4.Roman M, Jitaru P, Barbante C (2014). Selenium biochemistry and its role for human health. Metallomics 6, 25-54.

5.Martin JL (1995). Thioredoxin-a fold for all reasons. Structure 3(3), 245-250.

6.Atkinson HJ, Babbitt PC (2009). An atlas of the thioredoxin fold class reveals the complexity of function-enabling adaptations. PLOS computational biology, epub.

7. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal, BB (2010). Oxidative stress, inflammation and cancer: how are they linked? Free Radical Biology and Medicine 49, 1603-1616.

8. Barnham KJ, Masters CL, Bush AI (2004). Neurodegenerative diseases and oxidative stress. Nature Reviews Drug Discovery 3, 205-214.

9.Khanna KK, Jackson SP (2001). DNA double-stranded breaks: signaling, repair and the caner connection. Nature Genetics 27, 247-54.

10.Driessens N, Verteyhe S, Ghaddhab C, Burniat A, Deken XD, Sande J, Dumont JE, Miot F, Corvilain B (2009). Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ. Endocr Relat Cancer 16, 845-56.

11.Pan JL, Bardwell JCA (2006). The origami of thioredoxin-like folds. Protein Science 15(10), 2217-2227.